Amines enantiomerically enriched

Apart from tertiary amines, the reaction may be catalyzed by phosphines, e.g. tri- -butylphosphine or by diethylaluminium iodide." When a chiral catalyst, such as quinuclidin-3-ol 8 is used in enantiomerically enriched form, an asymmetric Baylis-Hillman reaction is possible. In the reaction of ethyl vinyl ketone with an aromatic aldehyde in the presence of one enantiomer of a chiral 3-(hydroxybenzyl)-pyrrolizidine as base, the coupling product has been obtained in enantiomeric excess of up to 70%, e.g. 11 from 9 - -10 ... 

In another example of enantioselective distillation, it was the enantiomeric mixture to resolve itself which contributed to create a chiral environment. Thus, non-racemic mixtures of a-phenylethylamine were enantiomerically enriched by submitting to distillation different salts of this amine with achiral acids [199]. 

One of the potentially most useful aspects of the imine anions is that they can be prepared from enantiomerically pure amines. When imines derived from chiral amines are alkylated, the new carbon-carbon bond is formed with a bias for one of the two possible stereochemical configurations. Hydrolysis of the imine then leads to enantiomerically enriched ketone. Table 1.4 lists some examples that have been reported.118... 

Petasis reported an efficient addition of vinyl boronic acid to iminium salts.92 While no reaction was observed when acetonitrile was used as solvent, the reaction went smoothly in water to give allyl amines (Eq. 11.54). The reaction of the boron reagent with iminium ions generated from glyoxylic acid and amines affords novel a-amino acids (Eq. 11.55). Carboalumination of alkynes in the presence of catalytic Cp2ZrCl2 and H2O affords vinylalane intermediates, which serve as nucleophiles in the subsequent addition to enantiomerically enriched... 

As an extension of the asymmetric hydrogenation of prochiral ketones to enantiomerically enriched alcohols, the reduction of imines has been a topic of interest in obtaining chiral amines of high enantiomeric purity. Several entries to enantiomerically enriched amines based on the approaches outlined above are available. These asymmetric hydrogenations have proved to be more difficult than those for prochiral ketones, but nevertheless show good promise. 

Ti-F bond and generate a Ti-H species when 99 was treated with phenylsilane. The chirality transfer may take place through imine insertion into the Ti-H bond, similar to that in the catalytic hydrogenation process.1000 The reaction can be carried out by the subsequent addition of imines. The corresponding silylated amines can be obtained and further converted to enantiomerically enriched amines upon acid treatment. For example, in the presence of 99, N-methylimine 100 undergoes complete hydrosilylation within 12 hours at room temperature, with 97% ee and up to 5000 turnovers.103... 

A wide range of carbon, nitrogen, and oxygen nucleophiles react with allylic esters in the presence of iridium catalysts to form branched allylic substitution products. The bulk of the recent literature on iridium-catalyzed allylic substitution has focused on catalysts derived from [Ir(COD)Cl]2 and phosphoramidite ligands. These complexes catalyze the formation of enantiomerically enriched allylic amines, allylic ethers, and (3-branched y-8 unsaturated carbonyl compounds. The latest generation and most commonly used of these catalysts (Scheme 1) consists of a cyclometalated iridium-phosphoramidite core chelated by 1,5-cyclooctadiene. A fifth coordination site is occupied in catalyst precursors by an additional -phosphoramidite or ethylene. The phosphoramidite that is used to generate the metalacyclic core typically contains one BlNOLate and one bis-arylethylamino group on phosphorus. 

Ahlbrecht and coworkers showed that the stereoselective alkylation of Af-cinnamyl (5 )-2-methoxymethylpyrrolidine (STdR), followed by hydrolysis, affords enantiomerically enriched 3-substituted phenylpropionaldehydes, as shown in Scheme 45. This method is analogous to the asymmetric alkylation of S AMP/RAMP hydrazones, as the anions are isoelectronic. The mechanisms of asymmetric induction for the two systems are probably similar. For the lithio cinnamyl amine, methylation can be optimized up to 97.5% ds. Most of the procedures in this paper include potassium tert-butoxide, so the cation in these examples may be potassium. Under these conditions, methyl, primary and secondary alkyl iodides typically afford the products with selectivities in the 90-93% ds range. 

Evans and co-workers demonstrated that rhodium-catalyzed allylic amination of enantiomerically enriched acyclic unsymmetrical allylic carbonates occurs with excellent regio- and enantiospedfidty (Tab. 10.5) [35]. Interestingly, while the classical nitrogen nucleophiles furnished allylic amination products in poor yield and with modest regioselectivity, the lithium anion of N-toluenesulfonyl-N-alkylamines proved optimal, in terms of nucleophilicity and basicity. 

Tab. 10.5 Enantiospecific rhodium-catalyzed allylic amination of enantiomerically enriched allylic carbonates.

The stereoselective construction of nitrogen heterocycles remains a topic of intense synthetic interest [39]. Evans and Robinson described the combination of the stereospecific aUylic amination with ring-closing metathesis as a strategy for the constmction of mono- and disubstituted azacycles, which they demonstrated with the stereospecific construction of cis- and tra s-2,5-disubstituted pyrrolines [40]. Furthermore, this approach provided an ideal system for the determination of whether the enantiospecific rhodium-catalyzed aUyhc amination with an enantiomerically enriched nucleophile experiences a matched and a mismatched reaction manifold. 

Jiang J, Yu J, Sun XX, Rao QQ, Gong LZ (2008) Organocatalytic asymmetric three-component cyclization of cinnamaldehydes and primary amines with 1,3-dicarbonyl compounds straightforward access to enantiomerically enriched dihydropyridines. Angew Chem Int Ed 47 2458-2462... 

The alkylation of metalated imines, hydrazones, 4,5-dihydrooxazoles, 4,5-dihydroisoxazoles, 5,6-dihydro-4/7-1,2-oxazines and 2,5-dialkoxy-3,6-dihydropyrazines (i.e., azaenolates) is a commonly used method in asymmetric synthesis of enantiomerically enriched aldehydes, ketones, spiroacetals, amines, /J-oxo esters, carboxylic acids, lactones, 1,3-amino alcohols, /(-hydroxy ketones and amino acids. 

A gold(III) catalyzed multicomponent synthesis of aminoindolizines was recently reported by Liu and Yan. This reaction of heteroaryl aldehydes, amines and alkynes took place under solvent-free conditions or in water and represented a high atom economic process. Especially noteworthy was the obtainment of N-indolizine-incor-porated amino acid derivatives by enantiomerically-enriched amino acid substrates without loss of enantiomeric purity [117]. 

Activated aziridines should be as useful as epoxides for carbon-carbon bond formation, with the advantage that the product will already incorporated the desired secondary aminated stercocentcr. To date, a general enantioselective method for the aziridination of alkcncs has not been developed. Eric Jacobsen of Harvard University (Angew. Chem. hit. Ed. 2004,43, 3952) has explored an interim solution, based on the resolution of racemic epoxides such as I. The cobalt catalyst that selectively hydrolyzes one enantiomer of the epoxide also promotes the addition of the imidc to the remaining enantiomerically-enriched epoxide. As expected, the aziridine 4 is opened smoothly with dialkyl cuprates. 

Two methods for the direct construction of enantiomerically-enriched allylic amines have recently been reported. John Hartwig of Yale University has developed (Angew. Chem. Int. Ed. 2004,43,4797) an Ir complex that effects the coupling of allylic carbonates such as 6 with aromatic amines to give the secondary amine in high . 

Pracejus et al. also demonstrated that diastereoselective addition of chiral amines to prochiral ketenes is possible [28, 32, 33] whereas attempts to catalytically produce enantiomerically enriched amides were frustrated by rapid uncatalyzed ad-... 

Catalysis by acids, which is only rarely effective for aliphatic amines but better suited to the less basic aromatic amines [334], can promote nucleophilic attack at the most strongly polarized C-0 bond of the epoxide (Scheme 4.75) [333, 334, 339]. Vinyl epoxides react with amines in the presence of Pd(0) under mild conditions to yield allylamines [340], If such reactions are performed in the presence of an enantiomerically pure ligand, racemic vinyl epoxides can be converted into enantiomerically enriched products of nucleophilic ring opening (last example, Scheme 4.75). 

Enantiomerically enriched a-hydroxy acetals are interesting synthons and can be transformed to a variety of chiral building blocks such as 1,2-diols, a-hydroxy acids, or 1,2-amino alcohols (Scheme 18.4). Whereas the oxidation to (f )-ethyl lactate was rather difficult and required the protection of the OH group, the reduction could be easily accomplished after hydrolysis of the acetal. No significant racemization was observed. With a boronic acid derivative and a secondary amine as described by Petasis and Zavialov,24 it was also possible to synthesize an amino alcohol with high diastereoselectivity. 

Discussion Taddol-catalyzed DA reactions provide simple and direct routes to functionalized cyclohexenones in enantiomerically enriched form. As with the HDA reactions, the best results were obtained when pure diene and dienophile were used, and the reaction temperature was rigorously maintained. Traces of moisture or acid impact negatively upon diene stability and product enantio-purities. One important advantage of the method is the commercial availability of both taddol catalyst 119 and the diene. The best substrates for the taddol-catalyzed DA reactions were a-substituted acroleins. This reactivity profile is complementary to that found for the secondary amine-based organocatalysis developed by MacMillan and co-workers, in which -substituted acroleins provided the best results [116]. 

Enantiomeric purities of compounds 111 were determined by HPLC using chiral column (Daicel-Chiralcel OD-H). This animation procedure is applicable to a variety of aryl-substituted imides (Table 3.11, entries b to f). The amination adducts 111 are all highly crystalline, and a single recrystallization of the product hydrazides led to enantiomeric enrichment (96 to 99 % ee). 

The ionic chiral auxiliary approach was also applied to the enantioselective photocylization of tropolone. Irradiation of salt crystals of tropolone ether carboxylic acid 29 with several chiral amines afforded the enantiomerically enriched secondary products 31 [52]. The best results were obtained with optically pure 1-phenylethylamine and l-amino-2-indanol, which gave optical yields in the 60-80% ee range depending on the extent of conversion. 

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